1. Field of the Invention
The disclosed invention relates to compositions and methods for promoting the maturation of monocytes. More specifically, the disclosed invention relates to the treatment of subjects suffering from cancer or infections with one or more monocyte maturation-promoting compounds.
2. Description of the Related Art
Monocytes, macrophages, and dendritic cells are of primary importance in the immune defense system of the body, playing a central role in the induction of the acquired immune response through their capacity to present antigen and regulate the function of T-lymphocytes.
Monocytes are mononuclear phagocytic white blood cells derived from the myeloid stem cells. Monocytes circulate in the blood stream and then move into tissues, at which point they mature into macrophages. Monocytes and macrophages are one of the first lines of defense in the immune process. Mononuclear phagocytes function as accessory cells in the recognition and activation phases of adaptive immune responses. Their main functions are to display antigens in a form that can be recognized by T lymphocytes and to produce membrane and secreted proteins that serve as secondary signals for T cell activation. Some mononuclear phagocytes may differentiate into dendritic cells, which play important roles in the induction of T lymphocyte responses to protein antigens.
During development, circulating monocytes migrate into essentially all body organs to form macrophages where they show highly heterogeneous phenotypes and functions based on tissue localization. During the immune process, signals are delivered to the bone marrow which promote the proliferation and release of promonocytes into the circulation where they are known as monocytes.
Numerous compounds such as colony stimulating factors and certain cytokines have been shown to regulate the development of mononuclear phagocytes. Granulocyte-macrophage colony-stimulating factor (GM-CSF), for example, is a cytokine which induces the differentiation, proliferation, and activation of a variety of immunologically active cell populations. GM-CSF facilitates the development of cell-mediated immunity, and recent studies suggest that a critical event in this action of GM-CSF is to induce the differentiation of monocytes into dendritic cells, which are potent antigen-presenting cells (Bell, D. et al., Adv Immunol, 72:255-324 (1999); Avigan, D., Blood Rev., 13:51-64 (2000)).
Because of the potency of compounds such as GM-CSF as immune adjuvants, particular interest has focused on their use to overcome the poor immunological response associated with cancer and chronic infections (for review, see Lawson, D., and Kirkwood, J. M., J. Clin. Oncol., 18:1603-1605 (2000)). For example, treatment with GM-CSF has been proposed to protect a substantial fraction of patients with high-risk malignant melanoma against relapse and death. In a study by Spitlier and co-workers, the median survival time of GM-CSF-treated melanoma patients (with stage III or stage IV disease) was increased by a factor of three as compared with that of matched control patients (Spitlier et al., J. Clin. Oncol., 18:1614-1621).
Despite these results, there is a need for improvement of monocyte maturation-promoting therapy in the treatment of neoplastic disease and chronic infections.